WO2025003945A1 - Procédé amélioré pour la préparation de 4-acétyl-2-méthyl-benzonitrile - Google Patents

Procédé amélioré pour la préparation de 4-acétyl-2-méthyl-benzonitrile Download PDF

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Publication number
WO2025003945A1
WO2025003945A1 PCT/IB2024/056261 IB2024056261W WO2025003945A1 WO 2025003945 A1 WO2025003945 A1 WO 2025003945A1 IB 2024056261 W IB2024056261 W IB 2024056261W WO 2025003945 A1 WO2025003945 A1 WO 2025003945A1
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WO
WIPO (PCT)
Prior art keywords
methyl
acetyl
benzonitrile
preparation
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2024/056261
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English (en)
Inventor
Rama Shankar
Misra NIMESH CHANDRA
Ravindra LANDGE
Nisar SAYYAD
Rahul Patil
Monish MORE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hikal Ltd
Original Assignee
Hikal Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hikal Ltd filed Critical Hikal Ltd
Publication of WO2025003945A1 publication Critical patent/WO2025003945A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups

Definitions

  • the present invention relates to an improved process for the preparation of 4-acetyl-2-methyl- benzonitrile of formula (I).
  • the present invention further provides an improved process for the preparation of isoxazoline derivatives using 4-acetyl-2-methyl-benzonitrile of formula (I) obtained by a process described herein.
  • the 4-acetyl-2-methyl-benzonitrile is a key intermediate for preparing isoxazoline derivatives such as Fluralaner, Lotilaner, Afoxolaner and Fluxametamide.
  • T and Y each independently represent a substituted aryl or a substituted heteroaryl
  • X represents a hydrogen atom or a halogen atom
  • the inventors of instant invention have developed an improved process for the preparation of 4-acetyl-2-methyl-benzonitrile to overcome the limitations of the prior arts in cost effective and industrially convenient way in high yield (>73%) in less cycle time with greater chemical purity (99%).
  • the instant process is performed on an industrial scale by using commercially available key raw materials such as 3-Methyl-4-fluoroacetophenone, sodium cyanide and a chelating agent such as citric acid.
  • the instant process involves the simple reactions conditions, isolation, and purification technique to obtain desired compound in pale yellow solid with better yield and good purity.
  • the 4-acetyl-2-methyl-benzonitrile obtained using said process is further utilized for the preparation of isoxazoline derivatives such as Fluralaner as disclosed in WO2013/021949 which is incorporated herein for reference.
  • In one aspect of the present invention provides a process for the preparation of 4-acetyl-2- methyl-benzonitrile of formula (I) by reacting 3-methyl-4-haloacetophenone, where halo is fluorine, chlorine, bromine, and Iodine with a solution consisting of sodium cyanide, chelating agent in a polar aprotic solvent.
  • X is halo
  • the present invention provides a 4-acetyl-2-methyl-benzonitrile having purity greater than 99%; more preferably greater than 99.5% as measured by HPLC.
  • the present invention relates to a process for the preparation of 4-acetyl-2- methyl-benzonitrile comprising the steps of: i) preparing a solution of sodium cyanide, chelating agent in a polar aprotic solvent, ii) heating a solution of step (a) at 65°C to 90°C, iii) adding 3-methyl-4-haloacetophenone of formula (II) iv) heating the reaction mixture of step (iii) at 90°C to 120°C, v) cooling the reaction mixture of step (iv), vi) filtering, and vii) recrystallisation the compound obtained in step (vi) using alcoholic solvent or hydrocarbon solvent.
  • compositions comprising, “comprising,” “includes,” “including,” “has,” “having,” “contains” or “containing,” or any other variation thereof, are intended to cover a non-exclusive inclusion.
  • a composition, a mixture, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, method, article, or apparatus.
  • “or” refers to an inclusive or and not to an exclusive.
  • indefinite articles "a” and “an” preceding an element or component of the invention are intended to be nonrestrictive regarding the number of instances (i.e., occurrences) of the element or component. Therefore “a” or “an” should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular indicates otherwise.
  • solvent refers to the single solvent or mixture of solvents.
  • the compound 4-acetyl-2-methyl-benzonitrile of formula (I) prepared by using the process described herein results purity having greater than 99%, preferably greater than 99.5%, and substantial percentage of known or unknown impurity as measured by HPLC.
  • the process for preparation of 4-acetyl- 2-methyl-benzonitrile of formula (I) which comprises: step (a) reacting a 3 -methyl-4-halo acetophenone with a solution containing sodium cyanide, chelating agent such as citric acid in presence of polar aprotic solvent; step (b) isolating; and step (c) recrystallization in alcoholic solvent or hydrocarbon solvent or combination thereof resulting in good yield (>73%) and better purity (>99.5%).
  • chelating agent uses in catalytic amount, which is selected from citric acid, Ethylenedinitrilo-tetraacetic acid (EDTA), Nitrilo triacetic acid (NTA), meso-2,3-dimercaptosuccinic acid (DMSA), and Gluconic Acid.
  • EDTA Ethylenedinitrilo-tetraacetic acid
  • NTA Nitrilo triacetic acid
  • DMSA meso-2,3-dimercaptosuccinic acid
  • Gluconic Acid is selected from citric acid, Ethylenedinitrilo-tetraacetic acid (EDTA), Nitrilo triacetic acid (NTA), meso-2,3-dimercaptosuccinic acid (DMSA), and Gluconic Acid.
  • citric acid is used in 1 to 5 %w/w ratio with respect to 3-methyl-4-haloacetophenone.
  • reaction is performed at a temperature of 80°C to 120°C and for 10-20 hours.
  • isolation step is performed by addition of water in reaction mixture, filtration, and subsequent purification by recrystallization.
  • recrystallisation process is comprising steps of: i) adding compound of step (b) in an alcoholic solvent or hydrocarbon solvent or mixture thereof. ii) heating the reaction mass till clear solution at 45 to 65°C for 1-2 hrs, iii) gradually cooling the reaction solution to from 65°C to -5°C and maintaining for 1- 2 hrs, iv) filtering the compound to obtain 4-acetyl-2-methyl-benzonitrile.
  • polar aprotic solvent is selected from ethyl acetate, acetonitrile, dimethylformamide, dimethyl sulfoxide and the like; preferably dimethyl sulfoxide.
  • alcoholic solvent is selected from methanol, ethanol, isopropanol, and the like.
  • hydrocarbon solvent is selected from toluene, hexane, pentane, cyclohexane and the like.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Toxicology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé amélioré pour la préparation de 4-acétyl-2-méthyl-benzonitrile de formule (I). La présente invention concerne en outre un procédé amélioré pour la préparation de dérivés d'isoxazoline à l'aide de 4-acétyl-2-méthyl-benzonitrile de formule (I) obtenu selon un procédé décrit ici.
PCT/IB2024/056261 2023-06-30 2024-06-27 Procédé amélioré pour la préparation de 4-acétyl-2-méthyl-benzonitrile Ceased WO2025003945A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202321044177 2023-06-30
IN202321044177 2023-06-30

Publications (1)

Publication Number Publication Date
WO2025003945A1 true WO2025003945A1 (fr) 2025-01-02

Family

ID=93937808

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2024/056261 Ceased WO2025003945A1 (fr) 2023-06-30 2024-06-27 Procédé amélioré pour la préparation de 4-acétyl-2-méthyl-benzonitrile

Country Status (1)

Country Link
WO (1) WO2025003945A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011104089A1 (fr) * 2010-02-25 2011-09-01 Syngenta Participations Ag Procédé de préparation de dérivés d'isoxazoline
CN109553528A (zh) * 2018-12-21 2019-04-02 荆门医药工业技术研究院 一种2-甲基-4-乙酰基苯甲酸甲酯的合成方法
WO2023012821A1 (fr) * 2021-08-01 2023-02-09 Zenfold Sustainable Technologies Private Limited Procédé pour préparer des médicaments de classe d'isoxazoline phényl-benzamide et de ses intermédiaires
CN116003293A (zh) * 2022-11-24 2023-04-25 八叶草健康产业研究院(厦门)有限公司 一种4-氰基苯乙酮的催化合成方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011104089A1 (fr) * 2010-02-25 2011-09-01 Syngenta Participations Ag Procédé de préparation de dérivés d'isoxazoline
CN109553528A (zh) * 2018-12-21 2019-04-02 荆门医药工业技术研究院 一种2-甲基-4-乙酰基苯甲酸甲酯的合成方法
WO2023012821A1 (fr) * 2021-08-01 2023-02-09 Zenfold Sustainable Technologies Private Limited Procédé pour préparer des médicaments de classe d'isoxazoline phényl-benzamide et de ses intermédiaires
CN116003293A (zh) * 2022-11-24 2023-04-25 八叶草健康产业研究院(厦门)有限公司 一种4-氰基苯乙酮的催化合成方法

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